Telomeric DNA functions to stabilize chromosomal ends and is progressively lost during cell division (the end replication problem), thus limiting cellular proliferative capacity.(1-3) The majority of cancers solve the end replication problem by expressing the telomere-synthesizing enzyme telomerase. A subset of the others utilizes a genetic recombination-based telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT).(4-7) The prevalence of ALT varies widely, but is found more often in cancers of the central nervous system (CNS) and of mesenchymal tissues than in common epithelial tumors.(8, 9)
A recent study of pancreatic neuroendocrine tumors (PanNETs) revealed that 43% harbored inactivating mutations in the ATRX or DAXX genes.(10) Notably, these mutations were mutually exclusive, indicating that they functioned in the same pathway. This mutual exclusivity was intriguing, as independent studies had shown that the proteins encoded by ATRX and DAXX interact with one another.(11) The ATRX gene encodes a large protein possessing a C-terminal helicase/ATPase domain placing it in the SNF2 family of chromatin remodeling enzymes.(12) Inherited mutations in ATRX cause X-linked alpha thalassemia/mental retardation syndrome, characterized by multiple developmental abnormalities in affected males.(13, 14) DAXX is a nuclear protein that interacts with numerous SUMO-modified proteins and plays a role in transcriptional repression.(15) The ATRX and DAXX protein complex has been suggested to play multiple cellular roles, including functioning in chromatin remodeling.(11, 76) Notably, the ATRX/DAXX complex was recently found to be required for the incorporation of the histone variant H3.3 at telomeres.(17-19) This histone chaperone activity may play a role in establishing or maintaining telomere stability, at least in mouse embryonic stem cells.(20, 21) Reducing either ATRX or H3.3 levels in these cells decreased the amount of heterochromatic protein HP1-alpha at telomeres and increased markers of telomere dysfunction.(20, 21) Epigenetic changes in telomeric and subtelomeric chromatin have also been shown to affect telomere length, as well as recombination at telomeres.(22-24)
There is a continuing need in the art to identify markers for diagnosis, prognosis, stratifying, and targeting of brain tumors.